Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling
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Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. / Ho, Jennifer E; Chen, Wei-Yu; Chen, Ming-Huei; Larson, Martin G; McCabe, Elizabeth L; Cheng, Susan; Ghorbani, Anahita; Coglianese, Erin; Emilsson, Valur; Johnson, Andrew D; Walter, Stefan; Franceschini, Nora; O'Donnell, Christopher J; Dehghan, Abbas; Lu, Chen; Levy, Daniel; Newton-Cheh, Christopher; Lin, Honghuang; Felix, Janine F; Schreiter, Eric R; Vasan, Ramachandran S; Januzzi, James L; Lee, Richard T; Wang, Thomas J; CARDIoGRAM Consortium.
in: J CLIN INVEST, Jahrgang 123, Nr. 10, 10.2013, S. 4208-4218.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling
AU - Ho, Jennifer E
AU - Chen, Wei-Yu
AU - Chen, Ming-Huei
AU - Larson, Martin G
AU - McCabe, Elizabeth L
AU - Cheng, Susan
AU - Ghorbani, Anahita
AU - Coglianese, Erin
AU - Emilsson, Valur
AU - Johnson, Andrew D
AU - Walter, Stefan
AU - Franceschini, Nora
AU - O'Donnell, Christopher J
AU - Dehghan, Abbas
AU - Lu, Chen
AU - Levy, Daniel
AU - Newton-Cheh, Christopher
AU - Lin, Honghuang
AU - Felix, Janine F
AU - Schreiter, Eric R
AU - Vasan, Ramachandran S
AU - Januzzi, James L
AU - Lee, Richard T
AU - Wang, Thomas J
AU - CARDIoGRAM Consortium
AU - Blankenberg, Stefan
PY - 2013/10
Y1 - 2013/10
N2 - The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
AB - The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
KW - Amino Acid Substitution
KW - Female
KW - Gene Expression
KW - Gene Expression Regulation
KW - Genetic Association Studies
KW - HEK293 Cells
KW - Humans
KW - Interleukin-1 Receptor-Like 1 Protein
KW - Interleukin-33
KW - Interleukins/genetics
KW - Male
KW - Middle Aged
KW - Models, Molecular
KW - Myelin and Lymphocyte-Associated Proteolipid Proteins/metabolism
KW - Myeloid Differentiation Factor 88/metabolism
KW - NF-kappa B/metabolism
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Prospective Studies
KW - Protein Structure, Tertiary
KW - Receptors, Cell Surface/chemistry
KW - Signal Transduction
KW - Transcription Factor AP-1/metabolism
U2 - 10.1172/JCI67119
DO - 10.1172/JCI67119
M3 - SCORING: Journal article
C2 - 23999434
VL - 123
SP - 4208
EP - 4218
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 10
ER -